Cystic Fibrosis-Related Diabetes Is Caused by Islet Loss and Inflammation

JCI Insight. 2018 Apr 19;3(8):e98240. doi: 10.1172/jci.insight.98240.

Abstract

Cystic fibrosis-related (CF-related) diabetes (CFRD) is an increasingly common and devastating comorbidity of CF, affecting approximately 35% of adults with CF. However, the underlying causes of CFRD are unclear. Here, we examined cystic fibrosis transmembrane conductance regulator (CFTR) islet expression and whether the CFTR participates in islet endocrine cell function using murine models of β cell CFTR deletion and normal and CF human pancreas and islets. Specific deletion of CFTR from murine β cells did not affect β cell function. In human islets, CFTR mRNA was minimally expressed, and CFTR protein and electrical activity were not detected. Isolated CF/CFRD islets demonstrated appropriate insulin and glucagon secretion, with few changes in key islet-regulatory transcripts. Furthermore, approximately 65% of β cell area was lost in CF donors, compounded by pancreatic remodeling and immune infiltration of the islet. These results indicate that CFRD is caused by β cell loss and intraislet inflammation in the setting of a complex pleiotropic disease and not by intrinsic islet dysfunction from CFTR mutation.

Keywords: Cell Biology; Diabetes; Endocrinology; Genetic diseases; Islet cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Animals
  • Cystic Fibrosis / etiology*
  • Cystic Fibrosis / genetics
  • Cystic Fibrosis / pathology
  • Cystic Fibrosis / veterinary
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics*
  • Diabetes Complications / genetics*
  • Diabetes Complications / veterinary
  • Diabetes Mellitus / epidemiology
  • Diabetes Mellitus / genetics*
  • Diabetes Mellitus / veterinary
  • Female
  • Gene Deletion
  • Glucagon / metabolism
  • Humans
  • Inflammation / complications
  • Inflammation / metabolism
  • Insulin / metabolism
  • Insulin-Secreting Cells / metabolism
  • Insulin-Secreting Cells / pathology
  • Islets of Langerhans / metabolism*
  • Male
  • Mice
  • Mutation

Substances

  • CFTR protein, human
  • Insulin
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Glucagon